2-33521973-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001139488.2(RASGRP3):c.387G>A(p.Met129Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,678 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RASGRP3 NM_001139488.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.89

Genes affected

RASGRP3 (HGNC:14545): (RAS guanyl releasing protein 3) The protein encoded by this gene is a guanine nucleotide exchange factor that activates the oncogenes HRAS and RAP1A. Defects in this gene have been associated with systemic lupus erythematosus and several cancers. [provided by RefSeq, Mar 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASGRP3	NM_001139488.2	c.387G>A	p.Met129Ile	missense_variant	7/18	ENST00000403687.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASGRP3	ENST00000403687.8	c.387G>A	p.Met129Ile	missense_variant	7/18	1	NM_001139488.2	P5
RASGRP3	ENST00000402538.7	c.387G>A	p.Met129Ile	missense_variant	8/19	1		P5
RASGRP3	ENST00000407811.5	c.387G>A	p.Met129Ile	missense_variant	6/17	1		A1
RASGRP3	ENST00000437184.5	c.387G>A	p.Met129Ile	missense_variant	7/7	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460678 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726582

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 16, 2021

The c.387G>A (p.M129I) alteration is located in exon 7 (coding exon 5) of the RASGRP3 gene. This alteration results from a G to A substitution at nucleotide position 387, causing the methionine (M) at amino acid position 129 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.30	T;.;T;.
Eigen	Uncertain	0.57
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.43	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;.;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.18	T;T;T;T
Sift4G	Benign	0.21	T;T;T;T
Polyphen		0.94	P;.;P;.
Vest4		0.55
MutPred		0.50		Loss of disorder (P = 0.0975);Loss of disorder (P = 0.0975);Loss of disorder (P = 0.0975);Loss of disorder (P = 0.0975);
MVP		0.71
MPC		0.36
ClinPred		0.80	D
GERP RS		6.0
Varity_R		0.33
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-33747040;